The long range objective of this laboratory is to understand the cellular and circuit basis of cognitive operations of the prefrontal cortex, the brain area closely associated with the executive functions of the human brain. In the past cycle of this grant, we have defined separate spatial and nonspatial visual processing domains associated with the dorsolateral and inferior prefrontal convexities, respectively. The goal of the present application is to functionally and anatomically dissect the intrinsic circuit mechanisms by which the prefrontal cortex performs its basic cognitive operations and to test the hypothesis that the prefrontal cortex is composed of content- constrained modules not only at the level of cytoarchitectonic areas (macroarchitecture) but also at the level of columns and microcolumns (microarchitecture). In Specific Aim number 1, powerful new multielectrode technology will be applied in vivo to the study of the dorsolateral prefrontal cortex to examine the dynamic interactions of ensembles of neurons with cue, delay and action-related response properties within and across cortical columns during spatial working memory tasks. This method will also allow analysis of the contributions of fast-spiking (putative interneurons) and regular spiking (putative pyramidal) neurons to these dynamic interactions and spatial memory field formation in the dorsolateral cortex. In Specific Aim number 2, the same powerful method will be applied to the object processing system of the inferior prefrontal cortex (IFC) to assess ensemble encoding in relation to the object/face response properties of IFC neurons. Specific Aim number 3 will complement the in vivo approach by employing whole cell patch clamp recording combined with infrared microscopy to visualize and directly study local circuits among functionally connected neurons in cortical slices. Collectively, these aims will explore a new level of functional anatomy in prefrontal cortex with the goal of providing mechanistic explanations of cognitive phenomena and insight into pathological processes of mental illness.